Managing the risk of tardive dyskinesia: based on an interview with William M. Glazer, MD.

Modern mental healthcare wouldn't exist without antipsychotics. These drugs led to a revolution in treatment delivery: Many patients with severe mental illnesses were able to throw off the chains of rudimentary treatments (sometimes literally) and become functioning members of society. But one of the serious problems associated with antipsychotic therapy is a neurologic condition called tardive dyskinesia. In the following article, based on an interview with William M. Glazer, MD, associate clinical professor of psychiatry at Harvard Medical School, how to best manage tardive dyskinesia in patients on antipsychotic therapy is explained.

**********

There are two generations of antipsychotics: The typicals are the older drugs, which were followed by a new breed in the late 1980s and early 1990s called the atypicals. A possible major side effect of antipsychotic therapy is tardive dyskinesia (TD), a neurologic syndrome caused by the long-term use of neuroleptic drugs such as antipsychotics. TD is characterized by repetitive, involuntary, purposeless movements. Orofacial features may include grimacing, tongue thrusting, jaw rolling, lip smacking, puckering and pursing, and rapid eye blinking. Rapid movements of the arms, legs, and trunk also may occur. Involuntary movements of the fingers may appear as though the patient is playing an invisible guitar or piano.(1) Symptoms range from mild (only visible to trained examiners) to severe and easily diagnosed. The movements can be embarrassing and even debilitating, affecting eating, breathing, and walking. People with TD might not only face the stigma of having a mental illness, they might also face the stigma of having a movement disorder. This can lead to serious quality-of-life issues.

[ILLUSTRATION OMITTED]

Etiology

Antipsychotics work by blocking dopamine in the brain, which often causes immediate side effects called extrapyramidal symptoms (EPS). EPS can be characterized as either hyperkinesias (excessive movements) or bradykinesias (diminished movements):

*** Examples of hyperkinesia include akathisia (restlessness) and tremor.

*** Examples of bradykinesia include parkinsonism, tremors, and rigidity. (2)

EPS is estimated to occur in nearly 50 to 60% of patients treated with typicals. (3,4)

In patients who develop EPS, according to the leading hypothesis, their brains adjust or compensate for the dopamine blockade by growing more dopamine receptors. It's thought that the brain actually overgrows dopamine receptors, and that overgrowth is thought to be the basis for TD. If a person has too many dopamine receptors, dopamine signals are sent to areas of the brain connected to movement. The overactive signals lead to excessive movements all over the body, typically involving the lips, tongue, face, jaw, extremities, and trunk. We don't know why these body parts are affected the most. The incidence of new TD has been estimated at 5% per year on antipsychotic therapy with typicals, (5,6) and this rate is cumulative so that after 20 years of exposure to the typicals, it has been estimated that almost 70% of patients will develop the condition. (7)

It's worth noting that in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, a landmark study sponsored by the National Institute of Mental Health that compared the typical antipsychotic perphenazine with the newer atypicals, patients with TD were not assigned to perphenazine, a "mid-potency" typical. (8) Perphenazine does not have the same EPS liability as the "high-potency" medications such as haloperidol but is believed to be associated with a higher EPS profile than the atypicals. Since EPS is thought to be a predictive measurement of TD, in the best interest of patients, investigators did not randomize patients with TD to perphenazine.

Tardive dyskinesia is a clinical diagnosis, i.e., there is no biologic test to confirm the condition; we must rely on history and medical reviews of systems to generate a differential diagnosis. Many excellent articles have been written on the differential diagnosis of TD. (9-12) One point worth noting is that some movements associated with parkinsonism can be confused with movements associated with TD. Movements associated with parkinsonism:

*** occur shortly after exposure to antipsychotics;

*** are tremors (repetitive, constant movements occurring usually more than four times per second); and

*** can involve dystonia (e.g., eyes rolling up and staying in a fixed position).

On the other hand, movements associated with TD:

*** occur months to years after exposure to antipsychotics (tardive, in fact, means "late onset");

*** are irregular; and

*** often are referred to as chorea (dance-like or writhing in nature) and occur fewer than two times per second.

Several formal scales are used to monitor and measure TD; the most frequently used and studied is the Abnormal Involuntary Movement Scale (AIMS), (13) which is reproduced at the end of this article.

At-Risk Populations

I have been involved in one of the few prospective incidence studies to identify risk factors associated with the typicals. (6) Some of the risk factors we identified were consistent with the views of most consensus groups, such as aging, dose of medication (the higher the dose, the greater the risk), and length of time exposed to the medication. These risk factors are discussed in other reports, as well. (14-16)

[ILLUSTRATION OMITTED]

We discovered some new findings, too: Blacks were found to be twice as likely to develop TD as whites, and left-handed people were found to have a reduced risk of TD. (6) We, like other investigators using the prospective incidence design, did not find that gender was a risk factor for TD. Other risk factors that have been suggested include developing EPS early on in treatment and having diabetes and other chronic medical illnesses.

Managing TD

TD cannot be prevented in a patient taking an antipsychotic; the risk only can be reduced. It's important to use the lowest effective dose of an antipsychotic. If TD is observed in a patient, the first step is to discontinue the agent, if warranted. (17) The clinician must consider that conditions such as schizophrenia and psychosis are difficult to treat, and thus sometimes it's a risk-benefit decision as to whether to stop the offending agent when movements appear. Some dietary supplements and pharmacologic interventions (such as benzodiazepines, calcium channel blockers, branch-chained amino acids, vitamin E, and beta blockers) may reduce symptoms, but there are no Food and Drug Administration-approved treatments for TD. Many of these interventions carry their own baggage (such as intolerable adverse events and the potential for abuse). (18) Trying a different antipsychotic might not reduce the risk of TD, either.

Because TD is a largely irreversible condition for which no adequate treatments exist, prevention is the best strategy. This is best achieved by using atypicals as the first choice for antipsychotic therapy because they have a lower risk of TD. (19) One of the main reasons atypicals were developed was to reduce the risk of TD. Since the atypicals were introduced in the late 1980s and early 1990s, the concern about TD and the number of cases have diminished considerably. In my own experience, the number of patients I have seen with TD has dropped by 80% to 90% since the atypicals became available. Therefore, most clinicians believe that using the atypicals is a first step in preventing or reducing the risk of TD. In light of this, it's troubling that a recent study (20) suggests that a higher percentage of African-Americans in low-income areas are disproportionately prescribed typicals, considering that blacks are twice as likely as whites to develop TD. (6)

Healthcare Policy Implications

Despite the atypicals' reduced risk of causing TD, some people have revisited using the typicals as first-line treatments for various reasons, such as their lower cost relative to atypicals. It would be unfortunate if policymakers mandated using the typicals as first-line treatments, because of their increased risk of TD. TD can be costly, leading to malpractice suits and increased healthcare utilization, not to mention the suffering of patients and families. Relying on atypicals as first-line treatments can reduce the risk of TD and its direct and indirect effects.

It's important to remember, however, that the atypicals have the same product information labeling for TD as the typicals; TD is still a risk, although reduced, with the atypicals. Therefore, clinicians should continually monitor their patients (e.g., with the AIMS) for TD.

Since the introduction of the atypicals in the late 1980s and early 1990s, fewer cases of TD have been seen. Images of patients with TD might have faded from the minds of policymakers and the general public, and newer clinicians probably have less experience with TD. This might explain some of the recent interest in returning to the use of typicals as first-line treatments. An analogy can be made to the public's experience with HIV: Cases of new HIV infection are now on the rise among young people who did not experience AIDS' scary emergence in the 1980s. But we do not want to return to the days when TD among patients on antipsychotics was more widespread. Therefore, in order to reduce the risk of TD, atypicals should remain the first-line treatments for schizophrenia.

References

1. National Institute of Neurological Disorders and Stroke. NINDS Tardive Dyskinesia Information Page. Updated February 9, 2005. Available at: www.ninds.nih.gov/disorders/tardive/tardive.htm.

2. Miller CH, Mohr F, Umbricht D, et al. The prevalence of acute extrapyramidal signs and symptoms in patients treated with clozapine, risperidone, and conventional antipsychotics. J Clin Psychiatry 1998;59:69-75.

3. Gelenberg AJ. Treating extrapyramidal reactions: Some current issues. J Clin Psychiatry 1987;48(suppl 9):24-7.

4. Tonda ME, Guthrie SK. Treatment of acute neuroleptic-induced movement disorders. Pharmacotherapy 1994;14:543-60.

5. Kane JM, Woerner M. Borenstein M, et al. Integrating incidence and prevalence of tardive dyskinesia. Psychopharmacol Bull 1986;22:254-8.

6. Morgenstern H, Glazer WM. Identifying risk factors for tardive dyskinesia among long-term outpatients maintained with neuroleptic medications: Results of the Yale Tardive Dyskinesia Study. Arch Gen Psychiatry 1993;50:723-33.

7. Glazer WM, Morgenstern H, Doucette JT. Predicting the long-term risk of tardive dyskinesia in outpatients maintained on neuroleptic medications. J Clin Psychiatry 1993;54:133-9.

8. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-23.

9. Cummings JL, Wirshing WC. Recognition and differential diagnosis of tardive dyskinesia. Int J Psychiatry Med 1989;19:133-44.

10. Task Force on Late Neurological Effects of Antipsychotic Drugs. Tardive dyskinesia: Summary of a Task Force Report of the American Psychiatric Association. Am J Psychiatry 1980;137:1163-72.

11. Jeste DV, Wyatt RJ. Understanding and Treating Tardive Dyskinesia. New York: Guilford Press, 1982:58-77.

12. Granacher RP. Differential diagnosis of tardive dyskinesia: An overview. Am J Psychiatry 1981;138:1288-97.

13. Munetz MR, Benjamin S. How to examine patients using the Abnormal Involuntary Movement Scale. Hosp Community Psychiatry 1988;39:1172-7.

14. Arana GW. An overview of side effects caused by typical antipsychotics. J Clin Psychiatry 2000;61(suppl 8):5-11.

15. Glazer WM. Review of incidence studies of tardive dyskinesia associated with typical antipsychotics. J Clin Psychiatry 2000;61(suppl 4):15-20.

16. Jeste DV. Tardive dyskinesia in older patients. J Clin Psychiatry 2000;61(suppl 4):27-32.

17. Stoner SC, Worrel JA, Jones MT, et al. Pharmacist-designed and -implemented pharmaceutical care plan for antipsychotic-induced movement disorders. Pharmacotherapy 2000;20:583-8.

18. Brasic JR, et al. Tardive dyskinesia. eMedicine J 2002;3(12).

19. Glazer WM. Expected incidence of tardive dyskinesia associated with atypical antipsychotics. J Clin Psychiatry 2000;61(suppl 4):21-6.

20. Kuno E, Rothbard AB. The effect of income and race on quality of psychiatric care in community mental health centers. Community Ment Health J 2005;41:613-22.

[GRAPHIC OMITTED]

AIMS EXAMINATION PROCEDURE

Either before or after completing the Examination Procedure, observe the patient unobtrusively, at rest (eg, in waiting room).

The chair to be used in this examination should be a hard, firm one without arms.

   1. Ask patient whether there is anything in his/her mouth (ie, gum,
      candy, etc) and if there is, to remove it.
   2. Ask patient about the current condition of his/her teeth. Ask
      patient if he/she wears dentures. Do teeth or dentures bother
      patient now?
   3. Ask patient whether he/she notices any movements in mouth, face,
      hands, or feet. If yes, ask to describe and to what extent they
      currently bother patient or interfere with his/her activities.
   4. Have patient sit in chair with hands on knees, legs slightly
      apart, and feet flat on floor. (Look at entire body for movements
      while in this position).
   5. Ask patient to sit with hands hanging unsupported. If male,
      between legs, if female, and wearing a dress, hanging over knees.
      (Observe hands and other body areas.)
   6. Ask patient to open mouth. (Observe tongue at rest within mouth.)
      Do this twice.
   7. Ask patient to protrude tongue. (Observe abnormalities of tongue
      movement.)
   8. Ask patient to tap thumb, with each finger, as rapidly as possible
      for 10-15 seconds: separately with right hand, then with left
      hand. (Observe facial and leg movements.)
   9. Flex and extend patient's left and right arms, one at a time.
      (Note any rigidity and rate it.)
**10. Ask patient to stand up. (Observe in profile. Observe all body
      areas again, hips included.)
**11. Ask patient to extend both arms outstretched in front with palms
      down. (Observe trunk, legs, and mouth.)
**12. Have patient walk a few paces, turn, and walk back to chair.
      (Observe hands and gait.) Do this twice.

**Activated movements

SUPPORTED BY ELI LILLY AND COMPANY

*MG38504